MINI REVIEW ARTICLE published: 09 January 2012 doi: 10.3389/fphar.2011.00092 Role of aldo–keto reductase enzymes in mediating the timing of parturition

Michael C. Byrns*

Department of Health Sciences, Illinois State University, Normal, IL, USA

Edited by: A better understanding of the mechanisms underlying parturition would provide an impor- Yi Jin, University of Pennsylvania, USA tant step toward improving therapies for the prevention of preterm labor. Aldo–keto reduc- Reviewed by: tases (AKR) from the 1D, 1C, and 1B subfamilies likely contribute to determining the timing Wei Ni, Michigan State University, USA of parturition through metabolism of progesterone and prostaglandins. Placental AKR1D1 Penelope Sheehan, University of (human 5β reductase) likely contributes to the maintenance of pregnancy through the Melbourne, Australia formation of 5β-dihydroprogesterone (DHP). AKR1C1, AKR1C2, and AKR1C3 catalyze the Michel A. Fortier, Laval University 20-ketosteroid and 3-ketosteroid reduction of progestins. They could therefore eliminate Hospital Center, Canada tocolytic progestins at term. Activation of the F prostanoid receptor by its ligands also *Correspondence: Michael C. Byrns, Department of plays a critical role in initiation of labor. AKR1C3 and AKR1B1 have prostaglandin (PG) F Health Sciences, Illinois State synthase activities that likely contribute to the initiation of labor. AKR1C3 converts PGH2 to University, Campus Box 5220, PGF2α and PGD2 to 9α,11β-PGF2. AKR1B1 also reduces PGH2 to PGF2α, but does not form Normal, IL 61790, USA. 9α,11β-PGF . Consistent with the potential role for AKR1C3 in the initiation of parturition, e-mail: [email protected] 2 indomethacin, which is a potent and isoform selective inhibitor of AKR1C3, has long been used for tocolysis.

Keywords: pregnancy, parturition, placenta, myometrium, prostaglandin metabolism, steroid metabolism, aldo– keto reductases

INTRODUCTION Progestins play a critical role in human pregnancy, as demon- Preterm birth (prior to 37 weeks gestational age) is the principle strated by the efficacy of progesterone in maintaining pregnancy cause of neonatal morbidity and mortality in the developed world. and of the progesterone receptor (PR) antagonist mifepristone in The United States has one of the highest rates of preterm births in terminating pregnancy and initiating labor (McGill and Shetty, the developed world, occurring in 12–13% of pregnancies (Gold- 2007; Iams et al., 2008; Kulier et al., 2011). In other species, enberg et al.,2008). Preterm deliveries account for 75% of perinatal a decline in circulating progesterone levels, mediated by dis- mortality and surviving preterm infants are at risk for neurolog- tinct pathways, precedes the onset of labor at term (Smith, 2007; ical, respiratory, and gastrointestinal complications (Goldenberg Zakar and Hertelendy, 2007). However, serum progesterone lev- et al.,2008; Iams et al.,2008). Treatments such as intravaginal prog- els do not decline during human pregnancies, suggesting that esterone can be effective at maintaining pregnancies in women at a different mechanism determines the timing of labor. The increased risk for preterm labor. Tocolytic therapies to stop active exact role of progesterone and its metabolites in determining labor do not delay parturition long enough to allow further fetal the timing of human labor remains a mystery. Proposed path- development, but do provide time for transportation to a hospital ways include paracrine regulation through increased myometrial with a neonatal intensive care unit (Iams et al., 2008; Mackeen expression of progesterone metabolizing enzymes and/or changes et al., 2011). However, tocolytics have a variety of side effects and in PR expression. In addition to direct actions of progesterone, there is not enough evidence of benefit to the infant to justify their actions of its metabolites are likely involved. In particular, 5β- use (Mackeen et al., 2011). dihydroprogesterone (5β-DHP) inhibits myometrial contractil- The mechanisms underlying the initiation of labor are poorly ity (Kubli-Garfias et al., 1979; Grazzini et al., 1998; Thornton understood, which has limited progress on therapies to maintain et al., 1999; Sheehan, 2006). The activities of human AKR1D1 pregnancy or stop preterm labor. The lack of a suitable animal and AKR1Cs suggest they play critical roles in mediating these model has limited progress toward understanding human partu- processes. rition (Smith, 2007;Veliça et al., 2009; Hill et al., 2010; Nanjidsuren Prostaglandins (PG) are also key mediators of parturition. et al., 2011). The roles of the placenta and other reproductive tis- Upregulation of PGH2 synthase 2 occurs late in pregnancy, result- sues in parturition, as well as specific steroid and prostaglandin ing in an increase in the synthesis of prostaglandins, particu- metabolites, differ considerably between mammalian species. Fur- larly the PGF2 isomers (Mijovic et al., 1999; Slater et al., 1999; thermore, the substrate specificities and expression levels of the Mitchell et al., 2005; Lee et al., 2008b). Activation of the F aldo–keto reductase (AKR) isoforms differ considerably between prostanoid (FP) receptor by prostaglandins stimulates cervical species. Given the discrepancies in mechanism between species, ripening and the initiation of labor (Kelly et al., 2003). AKR1B1 this review will focus on the AKRs and their substrates and and AKR1C3 are the enzymes that form the PGF2 isomers in metabolites in human pregnancy. humans.

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AKR1D1 IN THE MAINTENANCE OF PREGNANCY suggesting a second mechanism for the regulation of its activity. AKR1D1, human 5β-reductase, catalyzes the formation of 5β- The presence of other Δ4-ene steroids, particularly 11-deoxy- androstanes and 5β-pregnanes and contributes to the formation corticosterone and 4-androstene-3,17-dione (Chen et al., 2011), of bile acids in the liver (Charbonneau and Luu-The, 2001; Chen would be anticipated to potently decrease the formation of 5β- et al., 2011). Of particular relevance to pregnancy, AKR1D1 cat- DHP by AKR1D1. 4-Androstenedione levels are slightly elevated alyzes the conversion of progesterone to 5β-DHP (Figure 1; Char- during labor, while levels of its aromatase product estrone are very bonneau and Luu-The, 2001; Chen et al., 2011). 5β-DHP may be high during labor (Hill et al., 2010). Given the permissive ligand a key mediator of the pregnancy maintaining effects of proges- binding pocket of AKR1D1 (Di Costanzo et al.,2008; Faucher et al., terone. While levels of progesterone do not decrease during the 2008), it is likely that steroids that are not substrates, including final week of pregnancy, levels of 5β-pregnanes decline starting in estrogens, will serve as inhibitors. This inhibition might contribute week 31 (Hill et al., 2007). This decline appears to be largely the to the induction of labor by estrogens. result of decreased 5β-reduction, although increased downstream Although it is found in higher concentrations than 5β-DHP metabolism may also occur. Although 5β-DHP was proposed to throughout pregnancy, 5α-DHP formation does not appear bind directly to the oxytocin receptor and antagonize oxytocin to contribute to the timing of labor. 5α-DHP is completely binding (Grazzini et al., 1998), others have not been able to repli- unable to inhibit myometrial contractility in vitro (Kubli-Garfias cate this finding (Burger et al., 1999; Astle et al., 2003). 5β-DHP et al., 1979). Ratios of progesterone to 5α-DHP remain constant could also inhibit contractions through activation of the preg- throughout pregnancy and it appears that expression levels of 5α- nane X receptor (Mitchell et al., 2005), allosteric modulation of reductase enzymes remain elevated throughout pregnancy (Hill the GABA receptor (Putnam et al., 1991), or through some as yet et al., 2010). Much of the work that has investigated 5α-reduced unknown mechanism. Although the mechanism is uncertain, it pregnanes in pregnancy has focused on their neuroendocrine is clear that 5β-DHP limits myometrial contractility; it is signifi- effects, including their anxiolytic and anesthetic effects in the cantly more potent than progesterone at inhibiting the contraction mother, and their important role in protecting the developing ner- of myometrial cells in vitro (Kubli-Garfias et al., 1979; Thornton vous system of the neonate (Amin et al., 2006; Hirst et al., 2006; et al., 1999). Hill et al., 2011). Both 5α- and 5β-progestins, particularly allo- Elevated expression of AKR1D1 likely helps maintain human pregnanolone and pregnanolone, act as allosteric modulators of pregnancy. The placenta appears to be the major site of AKR1D1 GABAA receptors (Reddy, 2010). expression, although it is also expressed in the myometrium (Shee- han et al., 2005). The decline in 5β-DHP levels during labor are KETOSTEROID REDUCTION BY AKR1Cs IN PARTURITION accompanied by a significant decline in AKR1D1 mRNA levels. Members of the AKR1C subfamily are likely to help initiate labor The effect was particularly pronounced in the myometrium, which by catalyzing the formation of inactive progestin metabolites,lead- demonstrated a sevenfold reduction in AKR1D1 levels (Shee- ing to paracrine suppression of PR signaling (Figure 1). AKR1C1, han et al., 2005). Decreased synthesis of relaxatory pregnanes by AKR1C2, and AKR1C3 eliminate progesterone, 5α-DHP, and 5β- AKR1D1 may play an important role in the onset of labor. DHP through their 20-ketosteroid reductase activities (Penning AKR1D1 exhibits potent substrate inhibition by Δ4-ene et al., 2000; Jin et al., 2011). Furthermore, they possess substantial steroids due to binding in a non-productive conformation (Di 3-ketosteroid reductase activities that provide another pathway Costanzo et al., 2008; Faucher et al., 2008; Chen et al., 2011), for the metabolism of 5α-DHP and 5β-DHP (Jin et al., 2011). The 20α-, 3α-, and 3β-hydroxy-progestin products of AKR1C enzymes have reduced tocolytic activities and are substrates for elimination through glucuronidation or sulfation. The 3-hydroxy products, such as pregnanolone and allopregnanolone, are neu- roactive and could contribute to analgesic and anxiolytic effects in the mother and neuroprotection of the fetus (Steckelbroeck et al., 2004; Amin et al., 2006; Hirst et al., 2006; Reddy, 2010; Hill et al., 2011). The stereochemistry for the reduction of 3-ketosteroids varies between AKR1C isoforms and between 5α-DHP and 5β- DHP, while reduction of the ketone at the 20 position exclusively forms the 20α-stereoisomer (Jin et al., 2011). AKR1C1, AKR1C2, and AKR1C3 are expressed in reproduc- tive tissues, including the placenta, myometrium, and cervix (Nishizawa et al., 2000; Andersson et al., 2008; Lee et al., 2008a; FIGURE1|Progesteronemetabolism by AKR1D1 and AKR1Cs in Hevir et al., 2011). Placental tissues obtained from pregnancies pregnancy. AKR1D1 is likely to inhibit myometrial contractions through α formation of 5β-dihydroprogesterone, while AKR1C1, AKR1C2, and at term reduce progesterone to 20 -hydroxyprogesterone at five AKR1C3 are likely to stimulate contractions through the elimination of times the rate of placentas from the first trimester and there is a progesterone and 5β-dihydroprogesterone. AKR1D1 and the AKR1Cs might further increase in activity with the onset of labor (Milewich et al., also contribute to formation of neuroactive progesterone metabolites. The 1978; Diaz-Zagoya et al., 1979). It is not known whether expres- AKR1Cs would have similar activities toward 5α-dihydroprogesterone (not shown). sion levels of the AKR1C enzymes correspond to the observed activity. Expression of mRNA encoding AKR1C1 is elevated in

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the myometrium during spontaneous, but not oxytocin induced, throughout pregnancy, declining with gestational age until imme- labor (Lee et al., 2008a). AKR1C1 has the highest catalytic activity diately before the initiation of labor, when expression levels spike toward 20-ketosteroids, and this enzyme likely plays an impor- (Brodt-Eppley and Myatt, 1999; Olson et al., 2003). In sheep cor- tant role in the inactivation of myometrial progesterone during pus luteum and rat myometrium, expression of the FP receptor is spontaneous labor (Penning et al., 2000; Jin et al., 2011). Placen- upregulated by estradiol administration, while progesterone has a tal expression of AKR1C3 during pregnancy has primarily been suppressive effect, suggesting that steroids may regulate receptor examined in the context of its prostaglandin metabolizing effects levels during pregnancy (Hoyer et al., 1999; Dong and Yallampalli, and is discussed below. AKR1C2 expression in placenta is the low- 2000). est of the three peripheral AKR1C isoforms (Nishizawa et al.,2000) The traditional ligand for the FP receptor is PGF2α, although and the contribution of AKR1C2 to parturition may be less critical its stereoisomer 9α,11β-PGF2 is also a potent ligand (Mitchell than AKR1C1 and AKR1C3. et al., 2005). Levels of PGF2α in amniotic fluid are low through- Andersson et al. (2008) used intact tissues from combined out the first 36 weeks of pregnancy before rising during the hysterectomy and cesarean section to examine the role of AKR last few weeks of pregnancy (Lee et al., 2008b). Samples from mediated 20-ketosteroid reductase activity in cervical ripening. patients at term indicated a substantial increase in PGF2α from They observed mRNA transcripts corresponding to AKR1C1, no labor (250 pg/mL) to early labor (640 pg/mL) and advanced AKR1C2, and AKR1C3 in cervix, with AKR1C1 exhibiting the labor (4300 pg/mL), which was far greater than the increase in highest expression. Cervical tissue from patients in active labor PGE2 levels. These measurements were performed with a com- exhibited considerably faster progesterone 20-ketosteroid reduc- mercial immunosorbent assay with an antibody against PGF2α, tion relative to patients who were not in labor. However, cervical but cross-reactivity with 9α,11β-PGF2 was not ruled out. Similar expression of mRNA for the three AKR1C isoforms did not change levels of 9α,11β-PGF2 (400 pg/mL) were detected in amniotic fluid with labor onset. The increased reductase activity was proposed samples from patients undergoing labor at term using an assay to result from decreased expression of type 2 17β-hydroxysteroid with an antibody that had limited cross-reactivity with PGD2, but dehydrogenase, which catalyzes the opposing oxidation reaction not PGF2α, suggesting that both isomers may play an important (Andersson et al., 2008). role in labor (Mitchell et al., 2005). Elevated levels of 9α,11β- PGF2 (200 pg/mL) were detected in patients at term who were not undergoing labor, while levels of this isomer were suppressed in PROSTAGLANDIN SYNTHASE ACTIVITIES OF AKRs patients prior to 36 weeks, including those undergoing preterm Prostaglandins also regulate parturition. A critical signal in deter- labor. The absence of increased 9α,11β-PGF2 in preterm labor mining the timing of parturition is the release of calcium due to FP could be the result of low levels of PGD2 synthase or low AKR1C3 receptor activation. Unlike PGE2, which has receptors that inhibit activity. α contractions and others that induce them, PGF2 has only labor The enzymes responsible for the increased synthesis of PGF2 promoting effects (Brodt-Eppley and Myatt, 1999). The principle products at term have not been conclusively identified. However, phenotype of FP receptor knockout mice is the inability to deliver both of the proposed prostaglandin F synthases are aldo–keto young at term, which is rescued by the administration of oxytocin reductases (Smith et al., 2011; Watanabe, 2011). AKR1C3 forms (Sugimoto et al.,1997; Kawamata et al.,2008). A selective FP recep- both PGF2 isoforms. AKR1C3 has substantially higher catalytic tor antagonist inhibits myometrial cell contractility in vitro (Friel activity for the reduction of PGD2 to 9α,11β-PGF2 relative to its et al., 2005). Regulation of FP signaling is partially via control of other endogenous substrates, while the conversion of PGH2 to its expression levels and partially through the levels of its PGF 2 lig- PGF2α is also faster than for its steroid substrates (Matsuura et al., ands, which are determined by the expression of PGH2 synthase 1998; Suzuki-Yamamoto et al., 1999). Involvement of the AKR1B 2, and AKR1B1 and/or AKR1C3 (Figure 2; Mijovic et al., 1999; family has only recently been recognized, with the bovine AKR1B5 Slater et al., 1999; Mitchell et al., 2005; Lee et al., 2008b; Smith et al., isoform first shown to synthesize PGF2α (Madore et al., 2003). In 2011;Watanabe,2011). Transcript for the FP receptor is suppressed humans, AKR1B1 exhibits a higher catalytic activity for the con- version of PGH2 to PGF2α than AKR1C3, but it is not involved in the formation of 9α,11β-PGF2 (Kabututu et al., 2009). In addition to synthesizing PGF2α, a recent report indicates that in the absence of cofactor, AKR1B1 can catalyze the rearrangement of PGH2 to form PGD2; AKR1C3 did not exhibit this activity (Nagata et al., 2011). AKR1B1 and AKR1C3 are expressed in reproductive tissues during pregnancy and both likely synthesize PGF2 during preg- nancy. Both AKR1B1 and AKR1C3 were cloned based on placental DNA libraries (Grundmann et al., 1990; Dufort et al., 1999). Most FIGURE2|Prostaglandin metabolism by AKR1C3 and AKR1B1 in of the early work on AKR1B1 focused on its role in regulating pregnancy. Both AKR1C3 and AKR1B1 form PGF2α from PGH2, while glucose metabolism, although it has many additional endogenous α β AKR1C3 also forms 9 ,11 -PGF2 and AKR1B1 may also contribute to the substrates (Srivastava et al., 2005). Its roles in prostaglandin sig- formation of PGD2. Both PGF2 isomers will stimulate myometrial contractions through activation of the FP receptor. naling have only recently been described (Kabututu et al., 2009; Bresson et al., 2011). AKR1C3 also catalyzes the reduction of a

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wide variety of substrates in addition to prostaglandins (Mat- changes in other enzymes involved in upstream and downstream suura et al., 1998; Suzuki-Yamamoto et al., 1999; Byrns et al., metabolism. 2010). Although the contribution of AKR1C3 to labor initiation has Expression of AKR1B1 and AKR1C3 were recently examined not been the subject of much research, its enzymatic activities at the mRNA and protein levels in placenta (Breuiller-Fouché suggest an important role. Each of its enzymatic activities has the et al., 2010). Based on immunohistochemistry, both enzymes were potential to contribute to the initiation of parturition. AKR1C3 expressed throughout the fetal membranes, but the highest expres- can eliminate progesterone and its 5α- and 5β-reduced products sion was in chorionic trophoblasts and in decidual stromal cells. and can synthesize estradiol and both prostaglandin F2 isomers Western blot and quantitative RT-PCR indicated that AKR1B1 was (Byrns et al., 2010; Jin et al., 2011). Furthermore, it is potently primarily expressed in the choriodecidua, while AKR1C3 exhib- inhibited by the tocolytic drug indomethacin (Byrns et al., 2008). ited similar expression levels in both choriodecidua and amnion. It is expressed in several reproductive tissues during pregnancy, Lipopolysaccharide stimulation did not upregulate either pro- although it is not known whether expression levels change, except tein, suggesting that their expression levels do not contribute to in the cervix where it does not (Nishizawa et al., 2000; Andersson preterm labor induced by intrauterine infection. Changes in pla- et al., 2008; Breuiller-Fouché et al., 2010). Further investigation cental expression of these enzymes over the course of pregnancy into the role of AKR1C3 in parturition is needed. have not been examined. It remains to be seen whether targeting AKRs can have benefits in pregnancy. AKR1D1 inhibitors might be useful for inducing CONCLUSION cervical ripening or given along with oxytocin for the initiation Further research is needed to understand the contribution of the of labor. Inhibitors of the AKR1B and AKR1C enzymes might AKRs to the induction of normal labor. Furthermore, very lit- have benefits for the maintenance of pregnancy or for tocolysis. tle is known about the roles of the AKRs in mediating signaling However, a number of potential pitfalls make developing phar- during preterm labor, which may be very different than what macotherapies based on AKRs challenging. The lack of an animal occurs at term. Evidence supports a role for declining placental model makes testing these targets challenging. Given that mam- and myometrial AKR1D1 expression in the initiation of labor. mals have distinct mechanisms of parturition and AKR substrate Increased paracrine inactivation of progestins by AKR1Cs may specificities, it is not clear that effects in animal models will apply also be an important step in parturition. Formation of increased to human pregnancies. Another potential issue is that the AKR1C levels of PGF2 isomers stimulates labor, although a major unre- and AKR1D enzymes contribute to the synthesis of neuroac- solved question is whether changes in the placental expression of tive steroids, such as allopregnanolone and pregnanolone. Given AKR1B1 and/or AKR1C3 contribute to this effect. Changes in lev- the neuroprotective effects of these steroids, inhibition of these els of steroid and prostaglandin products could also result from enzymes in the fetal compartment may be undesirable.

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T., Katsuyama, M., Hasumoto, K., metabolite and spontaneous Zakar, T., and Hertelendy, F. (2007). Citation: Byrns MC (2012) Role of aldo– Murata, T., Hirata, M., Ushikubi, myometrial contractions in vitro. Progesterone withdrawal: key to par- keto reductase enzymes in mediating the F., Negishi, M., Ichikawa, A., and Lancet 353, 1327–1329. turition. Am. J. Obstet. Gynecol. 196, timing of parturition. Front. Pharmacol. Narumiya, S. (1997). Failure of Veliça, P., Davies, N. J., Rocha, P. 289–296. 2:92. doi: 10.3389/fphar.2011.00092 parturition in mice lacking the P., Schrewe, H., Ride, J. P., and This article was submitted to Frontiers prostaglandin F receptor. Science Bunce, C. M. (2009). Lack of func- Conflict of Interest Statement: The in Experimental Pharmacology and Drug 277, 681–683. tional and expression homology author declares that the research was Discovery, a specialty of Frontiers in Suzuki-Yamamoto, T., Nishizawa, M., between human and mouse aldo- conducted in the absence of any com- Pharmacology. Fukui, M., Okuda-Ashitaka, E., keto reductase 1C enzymes: implica- mercial or financial relationships that Copyright © 2012 Byrns. This is an Nakajima, T., Ito, S., and Watanabe, tions for modelling human cancers. could be construed as a potential con- open-access article distributed under the K. (1999). cDNA cloning, expres- Mol. Cancer 8, 121. flict of interest. terms of the Creative Commons Attribu- sion and characterization of human Watanabe, K. (2011). Recent reports tion Non Commercial License, which per- prostaglandin F synthase. FEBS Lett. about enzymes related to the synthe- Received: 29 November 2011; paper mits non-commercial use, distribution, 462, 335–340. sis of prostaglandin (PG) F2 (PGF2α pending published: 07 December 2011; and reproduction in other forums, pro- Thornton, S., Terzidou, V., Clark, A., and 9α,11β-PGF2). J. Biochem. 150, accepted: 20 December 2011; published vided the original authors and source are and Blanks, A. (1999). Progesterone 593–596. online: 09 January 2012. credited.

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